chr2-73448542-T-G

Variant names:

• chr2-73448542-T-G
• rs2037814
• NM_001378454.1:c.2015T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):​c.2015T>G​(p.Val672Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 1,613,818 control chromosomes in the GnomAD database, including 601,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.88 (58400 hom., cov: 30)
  • Exomes 𝑓: 0.86 (543517 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.272
• Publications: 38 publications found

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ALMS1 Gene-Disease associations (from GenCC):

• Alstrom syndrome

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ENSG00000295621 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2640652E-6).
• BP6: Variant 2-73448542-T-G is Benign according to our data. Variant chr2-73448542-T-G is described in ClinVar as Benign. ClinVar VariationId is 504918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378454.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	NM_001378454.1	MANE Select	c.2015T>G	p.Val672Gly	missense	Exon 8 of 23	NP_001365383.1	Q8TCU4-1
	ALMS1	NM_015120.4		c.2015T>G	p.Val672Gly	missense	Exon 8 of 23	NP_055935.4	Q8TCU4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALMS1	ENST00000613296.6	TSL:1 MANE Select	c.2015T>G	p.Val672Gly	missense	Exon 8 of 23	ENSP00000482968.1	Q8TCU4-1
	ALMS1	ENST00000484298.5	TSL:1	c.1889T>G	p.Val630Gly	missense	Exon 7 of 22	ENSP00000478155.1	A0A087WTU9
	ALMS1	ENST00000684548.1		c.1634T>G	p.Val545Gly	missense	Exon 6 of 21	ENSP00000507421.1	A0A804HJA5

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133048 AN: 151960 Hom.: 58344 Cov.: 30

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.921

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.774

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.852

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.868

Gnomad OTH AF: 0.880

GnomAD2 exomes AF: 0.865 AC: 215237 AN: 248768 AF XY: 0.860

Gnomad AFR exome AF: 0.900

Gnomad AMR exome AF: 0.949

Gnomad ASJ exome AF: 0.825

Gnomad EAS exome AF: 0.783

Gnomad FIN exome AF: 0.843

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.866

GnomAD4 exome AF: 0.862 AC: 1259705 AN: 1461740 Hom.: 543517 Cov.: 74 AF XY: 0.860 AC XY: 625394 AN XY: 727186

African (AFR) AF: 0.894 AC: 29933 AN: 33472

American (AMR) AF: 0.947 AC: 42321 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 21559 AN: 26130

East Asian (EAS) AF: 0.760 AC: 30176 AN: 39696

South Asian (SAS) AF: 0.829 AC: 71496 AN: 86254

European-Finnish (FIN) AF: 0.847 AC: 45217 AN: 53412

Middle Eastern (MID) AF: 0.853 AC: 4917 AN: 5766

European-Non Finnish (NFE) AF: 0.865 AC: 961772 AN: 1111924

Other (OTH) AF: 0.866 AC: 52314 AN: 60388

GnomAD4 genome AF: 0.876 AC: 133166 AN: 152078 Hom.: 58400 Cov.: 30 AF XY: 0.875 AC XY: 65035 AN XY: 74340

African (AFR) AF: 0.899 AC: 37324 AN: 41498

American (AMR) AF: 0.921 AC: 14065 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2835 AN: 3470

East Asian (EAS) AF: 0.774 AC: 3980 AN: 5140

South Asian (SAS) AF: 0.823 AC: 3960 AN: 4814

European-Finnish (FIN) AF: 0.852 AC: 9017 AN: 10586

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.868 AC: 59006 AN: 67980

Other (OTH) AF: 0.877 AC: 1853 AN: 2112

Alfa AF: 0.867 Hom.: 186137

Bravo AF: 0.882

TwinsUK AF: 0.858 AC: 3180

ALSPAC AF: 0.862 AC: 3323

ESP6500AA AF: 0.902 AC: 3459

ESP6500EA AF: 0.871 AC: 7180

ExAC AF: 0.863 AC: 104212

Asia WGS AF: 0.816 AC: 2839 AN: 3478

EpiCase AF: 0.870

EpiControl AF: 0.869

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Alstrom syndrome (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.031
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.22
DANN	Benign	0.38
DEOGEN2	Benign	0.0061	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00022	N
LIST_S2	Benign	0.098	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.27
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.63	T
Vest4		0.062
ClinPred		0.0014	T
GERP RS		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.056
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2037814; hg19: chr2-73675669; COSMIC: COSV52505498; COSMIC: COSV52505498;